Ann Thorac Surg 2001;72:1892-1897
© 2001 The Society of Thoracic Surgeons
Original article: general thoracic
Inhaled NO and prostacyclin during porcine single lung transplantation
Tiina L.S. Vainikka, MD*a,
Lasse J. Heikkilä, MD, PhDa,
Sinikka Kukkonen, MD, PhDb,
Hannu J. Toivonen, MD, PhDb
a Department of Cardiothoracic Surgery, Helsinki University Central Hospital, Helsinki, Finland
b Department of Anesthesiology, Helsinki University Central Hospital, Helsinki, Finland
Accepted for publication July 30, 2001.
* Address reprint requests to Dr Vainikka, Department of Cardiothoracic Surgery, Helsinki University Central Hospital, Haartmaninkatu 4, PO Box 340, 00029 HUS/Helsinki, Finland
e-mail: tiina.vainikka{at}hus.fi
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Abstract
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Background. Increased pulmonary vascular resistance (PVR) and decreased arterial oxygenation frequently complicate lung transplantation. Inhaled nitric oxide (NO) and aerosolized prostacyclin (PGI2) both dilate the pulmonary vasculature and improve oxygenation in adult respiratory distress syndrome. We investigated whether similar effects would occur during early reperfusion of a lung graft.
Methods. Eighteen pigs underwent left lung transplantation. We measured blood flow distribution, mean pulmonary artery pressure, PVR, and gas exchange in each lung separately. Animals were randomized into three groups to receive NO (10 ppm/30 minutes, 40 ppm/30 minutes), nebulized PGI2 (25 µg/mL/30 minutes, 50 µg/mL/30 minutes), or no drugs (control).
Results. In the transplanted lung, PVR was significantly higher than in the native lung. Pulmonary vascular resistance of the transplanted lung was lower in the NO and PGI2 groups in comparison with the control group. During the first hour of inhalation, NO decreased PVR more than PGI2. Neither drug improved oxygenation in the graft.
Conclusions. Nitric oxide and PGI2 decreased PVR of the transplanted lung slightly, but the effect did not produce a normal pressure in pulmonary vasculature.
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Introduction
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Early graft dysfunction is a common problem after lung transplantation and increases early morbidity and mortality. It is characterized by pulmonary hypertension, edema, and decreased oxygenation. Pulmonary vascular endothelial damage by oxygen-derived free radicals and by neutrophil-mediated mechanisms in reperfused lungs is considered to play a major role in the pathophysiology of this graft dysfunction [1, 2]. After lung transplantation, in the presence of endothelial dysfunction, local vasoconstrictors might explain the resistance of pulmonary hypertension to treatment with conventional doses of intravenously administrated pulmonary vasodilators [3, 4]. Higher doses will clearly induce systemic hypotension. Administration of pulmonary vasodilators by inhalation is therefore of great interest, but has been studied mainly in association with adult respiratory distress syndrome.
After human lung transplantation, inhaled nitric oxide (NO) attenuates pulmonary hypertension and improves arterial oxygenation [5, 6]. Nitric oxide induces pulmonary vasodilatation in well-ventilated lung areas and thereby reduces ventilation-perfusion mismatch. It is rapidly inactivated by red cells and is considered selective to pulmonary circulation. Furthermore, NO may also ameliorate ischemia-reperfusion injury by modulating leukocyte–endothelium interactions [7, 8]. Prostacyclin (PGI2) is also a potent pulmonary vasodilator. It has been used in the treatment of primary and secondary pulmonary hypertension associated with heart disease or heart operations. Intravenous PGI2 does not appear to be selective to pulmonary circulation and systemic hypotension may limit its use [9, 10]. It may also increase intrapulmonary shunt flow. These deleterious effects can be reduced by administration of PGI2 by inhalation [11].
The aim of the present study was to evaluate the effects of inhaled NO and PGI2 on pulmonary hemodynamics and gas exchange after porcine single lung transplantation.
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Material and methods
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We used 36 family-matched and size-matched pigs (weights about 20 kg) in this study, which was accepted by the local ethics committee. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" (National Institutes of Health publication 85-23, revised 1985).
The details of the study design have been described earlier [12]. Briefly, 18 pigs were premedicated with ketamine hydrochloride (500 mg intramuscularly) and then anesthetized with intravenous pentobarbital (10 mg/kg) and fentanyl (150 µg), and muscle relaxation was achieved with pancuronium (0.2 mg/kg). After intubation the animals were ventilated (Servo 900C; Siemens-Elema AB, Solna, Sweden) with 50% oxygen (tidal volume 12.5 mL/kg, 20 breaths per minute, positive end-expiratory pressure was 5 cm H2O). After median sternotomy, 400 IU/kg of heparin was given, both vena cavas were ligated, the inferior vena cava and the tip of left atrial appendix were cut, and the lungs were perfused with 1,000 mL of cold modified Euro-Collins solution (Fresenius AG, Bad Homburg, Germany) through a cannula in the main pulmonary artery. The lungs were cooled topically by irrigation of the chest cavity with cold saline solution. The trachea was clamped during manual midinflation, the heart-lung block was removed, and the left lung with an atrial cuff was excised free and stored immersed in cold (+4°C) saline solution for 3 hours.
Induction of the anesthesia of the 18 recipients was identical to that in the donor procedure, and anesthesia was maintained with a continuous intravenous infusion of pentobarbital (5 mg · kg-1 · h-1), fentanyl (10 µg · kg-1 · h-1), and pancuronium (0.2 mg · kg-1 · h-1). The pigs were intubated through a tracheotomy and then ventilated as described earlier. The left femoral vein and artery were cannulated with appropriate catheters for monitoring of central venous pressure and systemic arterial pressure (SAP), respectively. After administration of heparin (400 IU/kg), the left lung was removed through a median sternotomy. The atrial cuff of the donor’s left lung was anastomosed with the appendix of the recipient’s heart. The main pulmonary artery of the transplanted lung was not anastomosed, but was cannulated with a wire-reinforced cannula (24F) (as was the pulmonary artery of the native lung) to allow separate perfusions of both lungs. A 32F cannula was introduced into the right atrium for drainage of the venous return into a cardiotomy reservoir (Dideco; Mirandola, Italy), from which the perfusion lines were divided into two roller pumps (Gambro, Lund, Sweden) and then connected to the pulmonary artery cannulas. Pulmonary artery pressure was monitored through catheters introduced into each perfusion cannula, their tips advanced 1 cm out of the perfusion cannulas. Left atrial pressure (LAP) was registered through a catheter introduced into the left atrium. Blood samples for blood gas analyses (Radiometer ABL 700 series; Copenhagen, Denmark) were taken from two catheters: one in the inferior pulmonary vein of the transplanted lung and the other in the superior pulmonary vein of the native lung. The main bronchus of the transplanted lung was intubated and tubes from both lungs were connected with a Y-piece to the ventilator. The minute volume and the inhaled oxygen concentration of 50% were kept constant throughout the study. End-tidal carbon dioxide tension was measured from both intubation tubes with a capnograph (Datex, Helsinki, Finland).
Extracorporeal circulation
Once the extracorporeal circulation started, the total blood flow of 2 L/min was divided between the transplanted and the native lung by adjusting the roller pumps to generate equal mean pulmonary artery pressure (MPAP) in each lung. The systemic circulation was maintained by the recipient’s own heart. After a 15-minute stabilization period we registered the baseline hemodynamic measurements: SAP, LAP, central venous pressure, MPAP (transplanted/native), and blood flow distribution. To measure standardized pulmonary vascular resistance (PVR), we adjusted the blood flow to 0.75 L to each lung. We calculated PVR using the standard formula 
. Samples for blood gas analyses were taken from the pulmonary veins of the transplanted and the native lung.
The animals were randomized to three groups (n = 6, in each group) to receive either PGI2, NO, or only oxygen/air gas mixture (control). The study groups could not be blinded, because we could mount only one drug delivery system at a time on the ventilator.
Prostacyclin administration
For aerosolization of PGI2, we connected a jet nebulizer (Servo Nebulizer 945; Siemens, Erlangen, Germany) to Servo 900C ventilator. The nebulizer chamber (Cirrus; Intersurgical, Twickenham, United Kingdom) was in the inspiratory limb, 10 cm from the endotracheal tube. This nebulizer chamber delivers aerosol particles with a mass diameter of 1.6 µm for alveolar deposition. We dissolved 500 µg of PGI2 (epoprostenol, a synthetic derivate of prostacyclin, Flolan; Wellcome, London, United Kingdom) in glycine buffer to obtain two different concentrations: 25 and 50 µg/mL. The expiratory minute volume of the ventilator was constantly 5 L/min during administration of PGI2 through the jet nebulizer. After a 15-minute stabilization period PGI2 inhalation started at a concentration of 25 µg/mL for 30 minutes and continued thereafter at a concentration of 50 µg/mL for 30 minutes. The inhalation was then discontinued for 15 minutes and then repeated as above. The chambers were weighed before and after inhalation for the calculation of PGI2 dose delivered.
Nitric oxide administration
Nitric oxide was supplied in cylinders: 10,000 ppm of NO in nitrogen (Woikoski, Voikoski, Finland), and we used a Nomius C blender system (Nomius C, version 1.2; Gävle, Sweden) to deliver NO into the breathing circuit of the ventilator. Inspired NO and nitrogen dioxide (NO2) concentration were monitored constantly using a Nomius C chemiluminescence analyzer. After a 15-minute stabilization period NO inhalation started, first 10 ppm for 30 minutes and then 40 ppm for the next 30 minutes. The inhalation was interrupted for 15 minutes and then repeated as above. Methemoglobin in pulmonary arterial blood was measured every 15 minutes with a blood oximeter (Radiometer ABL 700 series; Copenhagen, Denmark). Hemodynamic variables were measured and samples for blood gas analyses were taken every 15 minutes for 2.5 hours after the onset of extracorporeal circulation. At the end of the experiment the animals were sacrificed. One half of the inferior lobe of the native and the transplanted lung was excised and dried in an oven at 60°C for 48 hours to determine the wet to dry (W/D) lung weight ratio.
Statistical methods
The results are expressed as mean and standard error of the mean (SEM), unless otherwise stated. Analysis of variance for repeated measures was used to detect differences between the three groups for the effects of drug, time, and lung (transplanted/native). Paired Student’s t test was used to detect the difference in W/D ratio between the transplanted and the native lung. Differences were considered significant at p less than 0.05.
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Results
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The weight difference between donor and recipient did not exceed 2 kg in any of the study groups. The duration of ischemia was 257 ± 1.6 minutes in the NO group, 267 ± 2.1 minutes in the PGI2 group, and 268 ± 2.1 minutes in the control group. During NO inhalation, NO2 concentrations were less than 0.2 ppm (NO 10 ppm) and 1.0 ppm (NO 40 ppm). Methemoglobin range was 0.5% to 2.1% during NO administration. The calculated PGI2 doses were 1.1 µg/min (25 µg/mL) and 2.1 µg/min (50 µg/mL).
Systemic hemodynamics
There were no differences in systemic mean arterial pressure (MAP) or systemic vascular resistance (SVR) between the PGI2 group and the control group. In the NO group MAP and SVR decreased slightly during the first study period. After discontinuation of the NO administration, MAP and SVR increased (p = 0.02), and this increase persisted throughout the rest of the study (Fig 1).
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Fig 1. Nitric oxide (NO) inhalation slightly decreased systemic mean arterial pressure (MAP) compared with prostacyclin (PGI2) or no drug inhalation (C = control). The drug inhalation started at 15 minutes, the dose was increased at 45 minutes (double for PGI2, quadruple for NO), and the administration was interrupted at 75 minutes. Similar drug inhalation was repeated beginning at 90 minutes.
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Pulmonary hemodynamics
The transplanted lung received only 15% to 30% of the whole blood flow, when the roller pumps were adjusted to maintain equal MPAP in each lung (Fig 2). During the first 45 minutes of the study the blood flow to the transplanted lung in the NO group exceeded that in the other two groups. This difference was, however, a result of the initial high resistance of the native lung in this group as indicated by measurement of PVR at standard flow (Fig 3). After 45 minutes there were no significant differences in the blood flow distribution between the three groups.
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Fig 2. The pulmonary blood flow to the transplanted lung measured at equal mean pulmonary artery pressure in the transplanted and the native lung was significantly smaller compared with the native lung (p < 0.001). Blood flow varied significantly during first 45 minutes between the nitric oxide (NO), the prostacyclin (PGI2), and the control groups (C), but after that time no significant differences in blood flow were noted between the groups. For the drug administration schedule, see Figure 1 legend.
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Fig 3. Pulmonary vascular resistance (PVR) was significantly higher in the transplanted lung (A) compared with the native lung (B). Nitric oxide (NO) and prostacyclin (PGI2) treatment significantly decreased PVR of the transplanted lung. The decrease was more effective in the NO group during the first 75 minutes, but after 15 minutes’ cessation of drug treatment (at 90 minutes in the figure), there were no differences between NO and PGI2 treatment. For the drug administration schedule, see Figure 1 legend. (C = control group.)
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Pulmonary vascular resistance of the transplanted lung was significantly higher compared with the native lung (p < 0.001) (Fig 3). Inhalation of 10 ppm of NO for the first time decreased PVR of the graft compared with the control group (p < 0.001). Increasing the dose to 40 ppm induced no additional attenuation of PVR. Neither dose of inhaled PGI2 reduced PVR of the transplanted lung significantly during the first part of the investigation. After discontinuation of the drug inhalation, PVR increased in the NO and PGI2 groups. During the second half of the study, PVR tended to increase in the control group. Nitric oxide and PGI2 each prevented this increase (p < 0.001, NO group versus control group; p < 0.01, PGI group versus control group) (Fig 3).
The initial PVR of the native lung in the NO group was higher than that in the other two groups. Inhalation of 10 ppm of NO abolished this difference. Pulmonary vascular resistance of the native lung of the control group was higher than PVR in the other two groups during inhalation of the drugs (p < 0.001) (Fig 3).
Gas exchange
In the venous blood returning from the native lung, PO2 was significantly higher compared with venous blood PO2 of the transplanted lung in all three groups (p < 0.001) (Fig 4). In the transplanted lungs there were no significant differences in pulmonary venous blood PO2 between the three groups. Pulmonary venous PO2 of the native lung decreased with time in the control group and was lower in comparison with the other groups (p < 0.01).
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Fig 4. Pulmonary venous blood oxygen tension was significantly higher in the native lung (B) than in the transplanted lung (A) (p < 0.001). Drug inhalation had no effect on blood oxygenation in the transplanted lung, but in the native lungs both drug inhalations resulted in better oxygenation with time, when compared with the controls (p < 0.01). For the drug administration schedule, see Figure 1 legend. (C = control group; NO = nitric oxide; PGI2 = prostacyclin.)
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Pulmonary vein carbon dioxide tension (PCO2) was significantly higher in the transplanted lung than in the native lung in all groups (Fig 5). The initial PCO2 at 15 minutes was similar in all transplanted lungs, but after that the PCO2 was significantly lower in the PGI2 group compared with the other groups (p < 0.001). In the native lung of the drug-treated groups PCO2 was also significantly lower than in the control group (p < 0.001).
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Fig 5. Pulmonary vein carbon dioxide tension was higher in the transplanted lung (A) than in the native lung (B). Prostacyclin (PGI2) treatment lowered PCO2 in the transplanted and the native lung (p < 0.001). For the drug administration schedule, see Figure 1 legend. (C = the control group; NO = nitric oxide.)
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Wet/dry weight ratio
At the end of experiment the native lung W/D ratios were 5.3, 5.7, and 5.7 in the PGI2, NO and control groups, respectively. The water content of the transplanted lungs was significantly higher, the corresponding W/D values being 8.7, 8.7, and 8.0, respectively. The drug treatment had no effect on the W/D ratio.
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Comment
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Early graft dysfunction, manifested as elevated PVR, pulmonary edema, and poor arterial oxygenation, frequently complicates lung transplantation. Several investigators have shown that pulmonary circulation after lung transplantation is resistant to treatment with conventional doses of intravenous pulmonary vasodilators. We wanted to find clinically applicable drugs that could reduce PVR and improve the blood oxygenation. For this purpose we developed a porcine model in which hemodynamic variables could be controlled and the responses of the graft compared with the responses of the normal lung in similar conditions. Thus far we have studied eg prostacyclin, prostaglandin E1, a thromboxane receptor antagonist (SQ 30741), and L-arginine given intravenously to the graft donor, in the pulmoplegia solution, or to the graft recipient during the reperfusion [12–14]. From the drugs tested thus far, only sodium nitroprusside has shown a slight vasodilatory effect [15].
Intravenous vasodilators carry a risk of inducing systemic hypotension [9, 10] and increasing pulmonary shunting, thus using high intravenous doses of these drugs is not recommended. Systemic vasodilatory action of nitrates can be avoided by administering NO as a gas into the airways. In addition to the vasodilation, also ventilation perfusion mismatch diminishes during NO inhalation as circulation increases only in the well-ventilated lung areas. This therapy has become popular in the treatment of different types of pulmonary damage, and several clinical studies favor the use of NO during lung and heart transplantations [5, 6, 16]. Administration of NO is, however, not without risks, for example, methemoglobinemia and production of the toxic metabolites NO2 and peroxynitrate (ONOO-). These risks increase during an oxidative stress such as reperfusion of a lung graft. The precise administration of NO also necessitates complex and expensive delivery technology.
The success with NO therapy to induce selective pulmonary vasodilation has prompted attempts to administer other vasodilators directly into the airways. Studies on acute respiratory distress syndrome, heart operations [11, 17], and experimental hypoxic vasoconstriction [18] have shown that inhaled PGI2 offers benefits similar to those of inhaled NO. Prostacyclin is easy to administer by inhalation and no serious side effects have been reported. In the present experiment we wanted to study whether PGI2 could be used as an alternative for NO after lung transplantation.
In our study 10 ppm of NO reduced PVR at the beginning of graft perfusion, whereas 40 ppm of NO offered no additional benefit. The concentrations of PGI2 in the nebulizer were high to ensure a sufficient drug deposition in alveolar spaces and to avoid large volumes of nebulized alkaline buffer in the lungs. Nevertheless, neither dose of PGI2 reduced PVR of the transplanted lungs during the first 90 minutes of the study. Pulmonary vascular resistance of the transplanted lung tended to increase toward the end of the study in the control group. Both drugs prevented this increase. The fact that the response of NO was blunted and the response to PGI2 became apparent only during the second half of the study may indicate involvement of multiple mechanisms responsible for increased PVR after lung transplantation. Studies on NO inhalation during canine left lung transplantation and minipig in situ left lung ischemia-reperfusion showed lower PVR and better oxygenation in comparison with no-drug-treated controls [19, 20]. Nitric oxide, however, did not improve these measurements with time, but prevented the deterioration of the lung graft and mortality that occurred in the control animals. Our drug-treated animals also had lower PVR, but we did not detect similar worsening in the control lungs. In those studies the other lung was isolated and the whole cardiac output was directed through the single lung graft, whereas we had two perfused lungs. The avoidance of hyperperfusion apparently protected our grafts from similar fast deterioration. Timing of the drug administration may be also important. In canine left lung transplantation, NO improved oxygenation only if the administration began before reperfusion of the graft [21]. Duration of ischemia may also change the efficiency of NO inhalation. Hermle and coworkers [22] demonstrated that NO suppressed pressor response, edema formation, and ventilation-perfusion mismatch in an isolated rabbit lung graft after 120 minutes warm ischemia, but had no beneficial effect when the ischemia time was 180 minutes.
Nitric oxide and aerosolized PGI2 are often considered to be void of systemic circulatory effects. During the first part of our study, however, NO decreased MAP slightly, whereas PGI2 inhalation had no effect on MAP. This finding is consistent with the discovery that even though NO is rapidly bound to blood components, part of it can later be released again as active NO.
The lung grafts develop edema because of the microvascular damage, and it is worsened further because transplanted lungs lack functional lymphatics to remove the interstitial edema fluid. In the present study neither NO nor PGI2 could prevent the increase in lung water content. Other investigators have obtained similar results [21, 23], whereas one study showed decreased water content with NO inhalation [19]. In that study hemodynamics of the NO-treated lungs seemed to be somewhat better, and diminished congestion could explain the result. Our system included extracorporeal circulation, which is used only in some clinical transplantations, and which may further increase lung water. The water content in our grafts was, however, in the same range as other studies on lung transplantation [19, 21]. In a study in which minipig lung was clamped from circulation, flushed with Euro-Collins, and reperfused, the water content was even higher than in our grafts [20]. This finding suggests that the presence of intact lymphatics may not have a major impact on the removal of the edema fluid during the first hours of reperfusion. Furthermore, the use of extracorporeal circulation for lung transplantation may not seriously worsen the lung damage.
Nitric oxide and PGI2 alleviated PVR of the transplanted lung slightly, but did not normalize pressure in the pulmonary vasculature. Several experimental studies have shown similar results, but in some studies NO treatment diminished graft deterioration [21, 23] and mortality [19], which occurred without NO treatment. However, in a randomized clinical study of 84 patients, prophylactic NO treatment did not show any improvement in physiologic variables or outcome [24]. Clearly more studies are needed to ascertain the possible beneficial effects and optimal usage of these drugs. Because of the ineffectiveness of these two strong vasodilators in reducing PVR, mechanisms other than active vasoconstriction may be tested in future studies.
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Acknowledgments
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The authors thank Hanna Oksanen, PhD, for statistical advice.
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Abstract
Introduction
